Ageing and amyloid-beta peptide deposition contribute to an impaired brain tissue plasminogen activator activity by different mechanisms

Cacquevel, Mathias; Launay, Séverine; Castel, Hervé; Benchenane, Karim; Chéenne, Simon; Buée, Luc; Moons, Lieve; Delacourte, André; Carmeliet, Peter; Vivien, Denis

doi:10.1016/j.nbd.2007.04.004

Cited by 58 publications

(58 citation statements)

References 35 publications

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“…Taken together, these data suggest that the cleavage of proneurotrophins, i.e., their conversion to mature protein, is compromised in aged rats. Indeed, it was recently established that following stimulation proneurotrophins are the main releasable forms (Yang et al 2009) and that the activity of the complex tissue plasminogen activator (tPA)/plasminogen cascade which is involved in their extracellular maturation decreases with age (Cacquevel et al 2007). We can therefore assume that impaired cleavage of precursor protein could also account for the decrease of mNGF in the cortex of aged animals, even though proNGF was abundantly present.…”

Section: Discussionmentioning

confidence: 99%

BDNF transcripts, proBDNF and proNGF, in the cortex and hippocampus throughout the life span of the rat

Perović

Tešić

Djordjevic

et al. 2012

AGE

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Neurotrophins are established molecular mediators of neuronal plasticity in the adult brain. We analyzed the impact of aging on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) protein isoforms, their receptors, and on the expression patterns of multiple 5′ exon-specific BDNF transcripts in the rat cortex and hippocampus throughout the life span of the rat (6, 12, 18, and 24 months of age). ProNGF was increased during aging in both structures. Mature NGF gradually decreased in the cortex, and, in 24-month-old animals, it was 30 % lower than that in adult 6-month-old rats. The BDNF expression did not change during aging, while proBDNF accumulated in the hippocampus of aged rats. Hippocampal total BDNF mRNA was lower in 12-month-old animals, mostly as a result of a decrease of BDNF transcripts 1 and 2. In contrast to the regionspecific regulation of specific exon-containing BDNF mRNAs in adult animals, the same BDNF RNA isoforms (containing exons III, IV, or VI) were present in both brain structures of aged animals. Deficits in neurotrophin signaling were supported by the observed decrease in Trk receptor expression which was accompanied by lower levels of the two main downstream effector kinases, pAkt and protein kinase C. The proteolytic processing of p75NTR observed in 12-monthold rats points to an additional regulatory mechanism in early aging. The changes described herein could contribute to reduced brain plasticity underlying the age-dependent decline in cognitive function.

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Section: Discussionmentioning

confidence: 99%

BDNF transcripts, proBDNF and proNGF, in the cortex and hippocampus throughout the life span of the rat

Perović

Tešić

Djordjevic

et al. 2012

AGE

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“…45,46 In support of this notion, previous studies that used SDS-PAGE-based zymography have reported decreased cerebral tPA/plasmin activity in brains of human patients with AD. [47][48][49] A downregulation of tPA activity is also evident in mouse models of AD, with several studies attributing the suppression of tPA activity to an increase in the expression of serine protease inhibitors. 25,48,50 Although we also show a decrease in tPA activity in the AD mouse brain, no obvious increases in the expression of the major inhibitors of tPA including PAI-1, PN-1 or neuroserpin was observed (Figure 6c).…”

Section: Discussionmentioning

confidence: 99%

“…[47][48][49] A downregulation of tPA activity is also evident in mouse models of AD, with several studies attributing the suppression of tPA activity to an increase in the expression of serine protease inhibitors. 25,48,50 Although we also show a decrease in tPA activity in the AD mouse brain, no obvious increases in the expression of the major inhibitors of tPA including PAI-1, PN-1 or neuroserpin was observed (Figure 6c). This dissimilarity may be because of the especially young age of the AD mice used in our study, as increases in PAI-1 levels 25 and decreases in tPA expression 51 arise at later stages in development.…”

Section: Discussionmentioning

confidence: 99%

Compartment- and context-specific changes in tissue-type plasminogen activator (tPA) activity following brain injury and pharmacological stimulation

Sashindranath

Samson

Downes

et al. 2011

Laboratory Investigation

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Tissue-type plasminogen activator (tPA) is a major protease of the central nervous system. Most studies to date have used in situ-or gel-based zymographic assays to monitor in vivo changes in neural tPA activity. In this study, we demonstrate that the amidolytic assay can be adapted to accurately detect changes in net tPA activity in mouse brain tissues. Using the amidolytic assay, we examined differences in net tPA activity in the cerebral cortex, sub-cortical structures and cerebellum in wildtype (WT) and tPA À/À mice, and in transgenic mice selectively overexpressing tPA in neurons. In addition, we assessed changes in endogenous net tPA activity in WT mice following morphine administration, epileptic seizures, traumatic brain injury and ischaemic stroke-neurological settings in which tPA has a known functional role. Under these conditions, acute and compartment-specific regulation of tPA activity was observed. tPA also participates in various forms of chronic neurodegeneration. Accordingly, we assessed tPA activity levels in mouse models of Alzheimer's disease (AD) and spinocerebellar ataxia type-1 (SCA1). Decreased tPA activity was detected in the cortex and subcortex of AD mice, whereas increased tPA activity was found in the cerebellum of SCA1 mice. These findings extend the existing hypotheses that low tPA activity promotes AD, whereas increased tPA activity contributes to cerebellar degeneration. Collectively, our results exemplify the utility of the amidolytic assay and emphasise tPA as a complex mediator of brain function and dysfunction. On the basis of this evidence, we propose that alterations in tPA activity levels could be used as a biomarker for perturbations in brain homeostasis.

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“…In AD, decreased tPA activity has been observed in AD models and its activity has been proposed to be controlled by a substantial increase of PAI-1. 82 Increased PAI-1 has been observed in APP transgenic mice 83 and in the CSF of AD patients. 84 Brain plasmin activity is also reduced in AD brains.…”

Section: The Relationship Between Pd and α-Synmentioning

confidence: 99%

Proteolytic clearance of extracellular α-synuclein as a new therapeutic approach against Parkinson disease

Park

Kim

2013

Prion

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Ageing and amyloid-beta peptide deposition contribute to an impaired brain tissue plasminogen activator activity by different mechanisms

Cited by 58 publications

References 35 publications

BDNF transcripts, proBDNF and proNGF, in the cortex and hippocampus throughout the life span of the rat

BDNF transcripts, proBDNF and proNGF, in the cortex and hippocampus throughout the life span of the rat

Compartment- and context-specific changes in tissue-type plasminogen activator (tPA) activity following brain injury and pharmacological stimulation

Proteolytic clearance of extracellular α-synuclein as a new therapeutic approach against Parkinson disease

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